Proteolysis inhibitors

FUT-187) is a naphthalenyllmidazolylaminobenzoate, an ENZYME INHIBITOR active as a (serine) PROTEASE INHIBITOR. It can be used as a proteolysis inhibitor in the treatment of postgastrectoiTty reflux oesophagitis, sepimostat methanesulfonate sepimostat. septide ([pGlu Pro ] Pe.n) is a substance P derivative, a TACHYKININ RECEPTOR AGONIST, selective at the NK -receptor subtype. It is used as a pharmacological tool. 

Neurokinin effects are terrninated by proteolysis. In vitro acetylcholinesterase (ACE) and enkephalinase can hydrolyze substance P. However, there appears to be no clear evidence that either acetylcholinesterase or ACE limit the actions of released substance P. Enkephalinase inhibitors, eg, thiorphan, can augment substance P release or action in some systems but the distribution of enkephalinase in the brain does not precisely mirror that of substance P. There appears to be a substance P-selective enzyme in brain and spinal cord. 

In contrast to retroviruses, proteolysis is an early event in the replication cycle of (+)-strand RNA viruses and both protease and polymerase inhibitors can be expected to halt the propagation of infectious viral particles from already infected cells. 

Zhang, Z., Winyard, P.G., Chidwick, K., Murphy, G., Wardell, M., Carrell, R.W. and Blake, D.R. (1994). Proteolysis of human native and oxidised ofi-proteinase inhibitor by matrilysin and stromelysin. Biochem. Biophys. Acta 1199, 224-228. 

Low levels of hypochlorous acid can function as a mediator in cell activation, induce NFKB heterodimer p50 /p65 in a T-lymphocytic cell line through proteolysis of IKB and pl05 inhibitors. Hypochlorous acid will also contribute to the release of TNFo in cellular supernatants of T-lymphocytes which are capable of commencing activation in non-induced cells (Schoonbroodt et ah, 1997). Hypochlorous acid can react with amines to produce chloroamines and N-chlorinated derivatives that have a long lifetime in plasma. Taurine, a sulfonated amino acid, will finally combine with these two products to reduce their toxicity. 

Griese M ci al. Reduced proteolysis of surfactant protein A and changes of the bronchoalveolar lavage fluid proteome by inhaled alpha 1-protease inhibitor in cystic fibrosis. Electrophoresis 2001 22 165-171. 

For example, with the crystal structure of the aspartyl protease from human immundeficiency virus (HIV-1) in 1989 came the opportunity to design molecules to block this important enzyme that acts as a molecular scissors. HIV is the virus responsible for AIDS. Essential to viral replication, the HIV protease cuts long strands composed of many proteins into the functional proteins found in mature virus particles. This proteolysis occurs at the very end of the HIV replication cycle (Figure 7-1). The three-dimensional structural information derived from the x-ray crystal structure, combined with computer modeling techniques, allowed chemists to design potent, selective inhibitors of the protease enzyme (Figure... 

In some instances it may be necessary to demonstrate that all traces of specific contaminants have been removed prior to final product filling. This would be true, for example, of many proteolytic inhibitors added during the initial stages of downstream processing to prevent proteolysis by endogenous proteases. Some such inhibitors may be inherently toxic, and many could (inappropriately) inhibit endogenous proteases of the recipient patient. 

Libraries of hundreds to thousands of spatially separate inhibitors have been prepared and screened to identify small molecule inhibitors of the human protease cathepsin D and the essential malarial proteases, plasmepsins I and II. The best inhibitors do not incorporate any amino adds and possess high affinity (Kj<5 nM).1241 Furthermore, these lead compounds were optimized by combinatorial methods for good physicochemical properties and minimal binding to human serum albumin. The optimized inhibitors effectively block cathepsin D-mediated proteolysis in human hippocampyl slices and are currently being used to evaluate the therapeutic potential of cathepsin D inhibition in the treatment of Alzheimer s disease. Additionally, the plasmepsin inhibitors serve as promising leads for the treatment of malaria. 

A calpain inhibitor, the DPK of N-dimethyltyrosine, was isolated from Streptomyces griseus and this compound showed activity in the calpain assay as described by Alvarez etal Calpain is a cytosolic protease regulated by calcium and is distributed in mammalian and avian cells. Calpain catalyzes proteolysis of target protein in cells, causing changes in metabolic processes such as the activation of protein kinase C, neuropeptide metabolism, and the activation of platelets. It is proposed that these inhibitors can be used in the treatment of neurodegen-erative diseases. 

The syndecan family of heparin sulfate proteoglycans (HSPGs) plays critical roles in several signal transduction pathways, and syndecan 3 intramembrane proteolysis is presenilin/y-secretase dependent (357). COX2 and COXl potentiate ABP formation through mechanisms that involve y-secretase activity. Sulindac sulfide and other NSAIDs (ibuprofen, indomethacin, R-flurbiprofen) selectively decrease the secretion of ABP independently of COX activity, probably via y-secretase inhibition (358-360). Pepstatin A methylester, sulfonamides, and benzodiazepines can also act as potent, noncompetitive, y-secretase inhibitors (335). These are but a few examples of the potential repercussions and biochemical consequences that the pharmacological manipulation of secretases in AD may bring about. 

As discussed in detail by Dillard et al. and by Mittman et al. the possible relationship of lysosomal proteases to chronic lung disease has been inferred from the finding of an increased incidence of emphysema in subjects deficient in serum ai>antitrypsin factor, an -globulin that can inhibit lysosomal proteases. (No effect of ozone on serum aj-antitrypsin inhibitor was noted in rabbits chronically exposed to ozone. ) Thus, an ozone-induced increase in concentrations of such enzymes in the lung might produce excess proteolysis and result in eventual chronic lung disease. However, the available evidence is inadequate to support the belief that such a process occurs in humans intermittently exposed to ozone. Further studies of this potential hazard would be of value. 

A more selective inhibition of NFkB can be achieved by transfecting cells with DNA coding for the natural inhibitor IkBo or a mutant IkB protein that lacks 36 N-terminal amino acids, and consequently becomes proteolysis resistant. In this way expression of adhesion molecules and monocyte adhesion and transmigration can be inhibited [87,88], The potentials and limitations of these latter types of therapy are however not fully understood as yet. Different transfection systems (adenoviral, retroviral, non-viral) are available for gene delivery purposes, all with their own potentials and restrictions. 

Selected entries from Methods in Enzymology [vol, page(s)] Sulfonylation reaction, 11, 706 reaction kinetics, 11, 707 second-order rate constants for inactivation of chymotrypsin, trypsin, and acetylcholine esterase by PMSE and related sulfonylat-ing agents, 11, 707 reactivation of PMS-chymotrypsin, 11, 710 as inhibitor [of calcium-activated factor, 80, 674 of cathepsin G, 80, 565 of crayfish trypsin, 80, 639 of elastase, 80, 587 of pro-lylcarboxypeptidase, 80, 465 of protease Re, 80, 691 of protease So, 80, 695 of protein C, 80, 329] proteolysis, 76, 7. 

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